Bone is a composite of biopolymers (principally collagen), and an inorganic component identified as carbonate hydroxyapatite, approximated as (Ca,Mg,Na,M)10(PO4,CO3,HPO4)6(OH,Cl)2 [See LeGeros R Z (1981). “Apatites in Biological Systems”. Prog Crystal Growth 4: 1-45; and LeGeros R. Z. (1991). Calcium Phosphates in Oral Biology and Medicine. Monographs in Oral Sciences. Vol 15. Myers H. M. (ed). Karger, Basel].
Calcium phosphate materials, principally hydroxyapatite (HA), beta-tricalcium phosphate (β-TCP), biphasic calcium phosphates, BCP (consisting of a mixture of HA and β-TCP in varying HA/β-TCP ratios) are commercially available as biomaterials for bone repair, augmentation or substitution. The principal advantages of calcium phosphate materials are: similarity in composition to the bone mineral, bioactivity, osteoconductivity and ability to form a uniquely strong interface with bone. Calcium phosphate materials are available as granules, blocks, coatings on dental and medical implants, and as cements.
Calcium phosphate cements (CPCs). The concept and potential advantages of an apatitic or calcium phosphate cement (CPC) as a possible restorative material was first introduced by LeGeros et al in 1982. [See LeGeros R. Z., Chohayeb A, Shulman A (1982). “Apatitic Calcium Phosphates: Possible Restorative Materials.” J Dent Res 61(Spec Iss):343]. This early formulation was based on mixing calcium-deficient or precipitated apatite (CDA) and calcium hydroxide with phosphoric acid. In 1987, Brown and Chow reported the first hardening CPC resulting from mixing tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrous (DCPA). There are presently numerous patents on CPC and several CPC commercial products. Compared to calcium phosphates that are available in particulate or block forms, CPC has the following desirable properties and decided advantages: malleability (allowing it to adapt to the site and shape of the defect and high bioresorbability (allowing it to be replaced by bone). The introduction of injectable calcium phosphate cements greatly improved the handling and delivery of the cements and opened up areas of new applications for the CPC. [Niwa S., LeGeros R. Z. (2002). Injectable Calcium Phosphate Cements for Repair of Bone Defects, In: Lewandrowski, K. A., Wise D. L., Taratola D. (eds). Tissue Engineering and Biodegradable Equivalents: Scientific and Clinical Applications. New York, Marcel Dekker, Inc. pp. 385-399.]
Calcium phosphate cement (CPC) systems consist of a powder and a liquid component. The powder component is usually made up of one or more calcium phosphate compounds with or without additional calcium salts. Other additives are included in small amounts to adjust the setting times, increase injectability, reduce cohesion or swelling time, and/or introduce macroporosity. Current commercial CPCs include two or more of the following calcium phosphate compounds: amorphous calcium phosphate (ACP), Cax(PO4)y.H2O; monocalcium phosphate monohydrate (MCPH), CaH4(PO4)2.H2O; dicalcium phosphate dihydrate (DCPD), CaHPO4.2H2O; dicalcium phosphate anhydrous (DCPA), CaHPO4; precipitated or calcium-deficient apatite (CDA), (Ca,Na)10(PO4,HPO4)6(OH)2; alpha- or beta-tricalcium phosphate (α-TCP, β-TCP), Ca3(PO4)2; and tetracalcium phosphate (TTCP), Ca4P2O9. Other calcium salts include: calcium carbonate (CC), calcium oxide or calcium hydroxide (CH), calcium sulfate hemihydrate (CSH), and calcium silicate. The liquid component may be one or combinations of the following solutions: saline, deionized H2O, dilute phosphoric acid, dilute organic acids (acetic, citric, succinic), sodium phosphate (alkaline or neutral), sodium carbonate or bicarbonate, sodium alginate, sodium bicarbonate, and/or sodium chondroitin sulfate. The setting reaction product(s) obtained after the cement has set is (are) determined by the composition of the powder component and composition and the pH of the liquid component. The setting time (which can range from 10 to 60 min) is determined by the composition of the powder and liquid components, the powder-to-liquid ratio (P/L), proportion of the calcium phosphate components (e.g., TTCP/DCPA ratio) and the particle sizes of the powder components. Apatitic calcium phosphate or carbonate-containing apatite (carbonatehydroxyapatite, CHA) with crystallinity (crystal size) similar to that of bone apatite can form before implantation when the cement sets or can result from the in vivo hydrolysis of the non-apatitic setting product (e.g., DCPD) after implantation.
The currently available commercial CPCs set as a dense mass and therefore suffer from some shortcomings such as absence of interconnecting macroporosity and slow rate of bioresorbability. Appropriate macroporosity (100-300μ) in the cement is critical to allow for vascularization and tissue ingrowth to take place and thus facilitate the formation of new bone. In addition, appropriate porosity allows the incorporation of drugs and therapeutic agents (e.g, antibiotics, antiresorption agents for osteoporosis; anticancer agents, etc) or growth factors (e.g., bone morphogenetic proteins; BMPs and other bioactive molecules). Appropriate rate of bioresorbability is critical for the timely replacement of the cement with new bone.
Several methods of introducing macroporosity in the CPC have been recommended. These methods include: introduction of resorbable fibers, e.g., polygalactin; addition of soluble salts (e.g. calcium chloride and sodium or potassium hydroxide; addition of pore forming agents (e.g., sugar, NaHCO3, calcium salts); using frozen sodium phosphate (Na2HPO4) solution particles; adding acidic sodium phosphate (NaH2PO4) solution to NaHCO3; and providing acid (citric acid) and base (NaHCO3). These methods produce macroporosity from the liberation of CO2 during the reaction of acid and NaHCO3.